Thiazole substituted by a primary alkylamino group



Patented Nov. 12, 1935 UNITED STATES PATENT OFFICE THIAZOLE SUBSTITUTED BY A PRIMARY ALKYLAMINO GROUP No Drawing. Application August 18, 1932, Serial No. 629,398

5 Claims. (01. 260-44) In my copending application Serial No. 629,397, filed August 18, 1932, I have described and claimed the products of the general Formula I, which are obtainable by the following reaction:

The intermediate products of the general formula Ia are obtainable by a reaction between a ketone having in its tautomeric enol form the general formula:

wherein R stands for a halogenated aliphatic radical which may be substituted by aryl radicals, and wherein X stands for hydrogen or alkyl or aryl or aralkyl, and wherein I-Ilg stands for either chlorine, bromine or iodine, and a thioamide compound containing the grouping as has been described and claimed in my copending application Serial No. 629,396.

In the above general Formulae I and Ia R1 may represent a large variety of organic radicals such as alkyl, hydroxyalkyl, alkoxy alkyl, aryl, aralkyl, alkyl substituted aryl, hydroxyaryl, alkoxy aryl; the aryl radical standing alone or in any of the combinations above enumerated may be substituted by various radicals such as hydroxyl, bromine, chlorine, iodine, O-alkyl. More specifically R1 may represent the phenyl group which may contain one or more free or substituted hydroxy groups, which hydroxy groups may be in ortho-, metaor para-position. RzA stands for a compound which has at least one reactive hydrogen or alkali metal atom designated as A. R

stands for a halogenated aliphatic radical and X for either H, or alkyl, aryl or aralkyl.

In particular, when RzA in the above general Formula Ia stands for an alkali metal salt of an organic compound containing carboxylic acid groups, and also containing a methylene group, 5 both hydrogen atoms of which, designated as A, are reactive, such compound being, for instance, an alkali metal salt of an ester of malonic acid and of higher homologues thereof, or of a B-ketocarbonic acid ester containing a methylene group 10 as above characterized, such compound being, for instance, aceto acetic acid, and when R1 stands for a phenyl radical which may contain one or more free or substituted hydroxy groups and which hydroxy groups may be in ortho-, metaor 15 para-position, the respective compounds I obtainable by the above reaction will be characterized by the following constitution:

L V l wherein R has the above given signification, and 25 wherein X stands for either hydrogen, or alkyl, aryl or aralkyl, and wherein it stands for one of the numbers I and 2, and wherein R2 stands for a radical of an organic compound containing carboxylic acid groups and containing a methylene 30 group both hydrogen atoms of which are reactive, and at least one of which hydrogen atoms has been eliminated by the formation of a linkage between a carbon atom of an aliphatic radical R and the carbon atom of the methylene group. 35

As an example, 2-phenylthiazole-4-methyl malonic acid of the formula:

may be mentioned; it has been described in my 45 copending application Serial No. 629,397, filed August 18, 1932.

I have now found that these malonic acid derivatives of l-methylthiazoles can be converted in which the phenyl radical may contain one or Nomelnclature and constitution (T=the thiazole nucleus) I. 2-phenylthiazo1e4-p-propi0nic acid HOOCCHZCHZTCGHS. 5

II. Ethyl 2-phenylthiazole-p-propionate more free or substituted hydroxy groups, which C2H5OOCCH2CH2TC6H5. hydroxy groups may be in ortho-, metaor paraposition. Such compounds are bases of the phez'phenyltmazole4"5prp1nhydmz1de nylethylamine type H2NNHCOCH2CH2TC6H5. H2N9H2 OHPC H5 IV. 2-phenylthiazole-4-,B-propionazide in which the aliphatic part is linked to the benzene nucleus by the thiazole ring. It is known 7 NsOCCHzCHzTCsHs. that this nucleus and the side-chain substitutions r 4- 1 .-urea in a base of the Type V above bring about physio- D1 (2 phenylthmzole ethy gym logical effects leading to products of therapeutical C6H5TICH2CHzNHCONHCHZCHzTCsHs. value.

I have now found that also the amines of the 2'phenylthlazole'4'ethylphthahmlde Type IV are substances of decided pharmaceutical C6H4 CO zNCHzCHZTCGHi value.

The following examples illustrate the process 2-pheny1thiazo1e-4-ethylamine of preparing the amines of the Type IV and the products thus obtainable. H2NCH2CH2TC6H5.

Experimental data Nitrogen Number M. 1. O. B. P. O. Crystal form Oalcd Found Hydrochloride, 146-147 (2-3 mm.)

EXAMPLEl EXAMPLE 2 2 phenylthiazole 4 ethyzamme Dz- (Z-phenylthtaeoIe-el) -1,3-zsopropylamzne n s fi NHioH2oHl-o c-o6H5 (MP0 N (Idem N 112Nofi This compound is prepared by the following g course of reactions: GH2C /O-C&Hfl

2-Phenylthiazolel-methyl-malohic acid heated N/ to its melting point yields under evolution of car- This com ound 1s iepared by a lying the hon dloxld? 2'phenyltmazole''fi'propmm? t course of resctions des zzribed in Exanig le 1 to di- This acid 1s esterified with ethyl. alcohol yl'ildmg (2-phenylthiazole-4-methyl) -malonic acid. The ethyl f t i The esphysical properties of the intermediate products ter 1s digested in alcohol with a shght excess of and of the resulting end product di-(Z-phenyl- 40% hydrazine hydrla'te yielding thiazolel)-1,3-isopropylamine are described in niylthiazole'4'fi'pr9pmn'hydrazlde' 1:118 hydra the following table in which also the analytical zide is converted into the corresponding Z-phedata are 60 nylthiazolel- 3-propionazide by diazotation in glacial acetic acid solution. By Warming the azide in dilute acetic acid solution, di-(Z-phenylthiaz0le-4-ethy1)-sym. urea is obtained. The urea compound is heated with phthalic anhydride to higher temperature as long as carbon dioxide is evolved yielding 2-phenylthiazole-4-ethyl-phthal imide. The phthalimide is then digested in alcohol with 40% hydrazine hydrate solution and the 2-phenylthiazole-4-ethylamine of the above structural formula is obtained.

In the following table are given for convenience the physical and analytical data for the intermediate products mentioned above and for the end product Z-phenylthiazole--ethylamine.

constitution (T=the thiaeole nucleus) 1. Ethyl di-(2 phenyIthiaZOle I-methyI)-acetate (C2H5OOC) CH(CH2TC6H5) 2.

N omenclature and a II. Di-(2-phenylthiazole-4-methyl)-acetic acid 2,020,650 VII. Di-( 2 -phenylthia zle- 4 1.3 -isopropy1- VII. 2-p-methoxyphenylthiaz0le-4 -ethy1amine amine H2NCH(CH2TC6H5)2. NH2CH2CH2TC6H4OCH3.

Experimental data 5 Nitrogen Number M. P. O. B. P. O. Crystal form 1 Calcd Found 272 at 2-3 mm s-159 Hydrochloride VIII. 2-p-hydroxyphenylthiazole-4-ethylamine H2NCH2CH2TC6H4OH.

Experimental data Nitrogen Number M. P. o. B. P. "c. Grystalform Calcd Found I Needles 11.--- III Needles 1v V- Prisms or plates $5 eedl s VIII: 'ii'ie'r'il''rili'' 6156515; 211511: 'b'fiirfiiITsf EXAMPLE 3 EXAMPLE 4 4O 2-11-hydromyphenylthiazoZe-ei-ethylamine S 2- (3,4-dimethoayphenylthiazole) -4-ethylamine HN-OH OH 0 --OH z 2 (RH V N HzN-CHz-OH:C c oorn By applying the course of reactions as de- \N/ I scribed in Example 1 to 2-p-methoxyphenylthia- (PCB: zo1e-4-methy1 malonic acid, 2-p-methoxypheny1- thiazolel-ethylamine is obtained which upon This compound is prepared by applying the treating with 48% hydrobromic acid by refluxing during 3 hours yields 2-p-hydroxyphenylthiazole- 4-ethylamine. It was isolated in form of the hydrochloride. The physical properties of the intermediate products and of the end product hycourse of reactions as described in Example 1 to 2-(3,4-dimethoxyphenylthiazole-4-methy1) malonic acid. The physical properties of the intermediate products and'of the resulting end product 2 3,4 -dimethoxyphenylthiazo1e) 4-ethy1am'ine drochloride of 2-p-hydroxyphenylthiazo1e-4-ethare described in the following table in which also ylamine are described in the following table in the analytical data are given:

which also the analytical data are given:

Nomenclature and constitution (Tzthe tin-azure Nomenclature and constitution (T=the thiazole nucleus) nucleus) I. 2-p-methoxyphenylthiazole 4 -fi-D D I. 2-(3,4-dimethoxyphenylthiazole) -4-c-pro- I-I(I)IOClarissa-12giti xlgigghenyltm'azole 4' B pro pionic acid HOOCCH2CH2TC6H3(OCH3) 2.

II. Ethyl 2 (3,4 dimethoxyphenylthiazole) 32; fiwmpmm l-fi-propionate C2H5OOCCI-I2CH2TC6H3(OCH3)2. hydrazid HzNNI-ICOCIzCFzTCsI-ROCI-Is 2 34'dimethoxyphenylthiamle)'4"3'pr' pionhydrazide H2NNHCOCH2CH2TC6H3 (00113) 2.

IV. 2 -p-methoxyphenylth1azole-4-5prop1ona- Zide N3COCH2CH2TC6H4OCH3' IV. 2- (3,4-d1methoxyphenylth1azo1e) -4-,6-pro- V. Di- (2 -p-methoxyphenylthiazole 4- ethyl) plonazlfie N3COCH2 CH2TC6H3(0CH3) 7O Sym urea V. D1 2 (3,4 dimethoxyphenylthiazole) 4 CH3OCsH4TCI-I2CH2NH ethyl-sym-ww VI. 2-p-methoxyphenylthiazole-4-ethy1phthal- (CHsO) 2C6H3TCH2CH2NH imide Cal-14(CO2) NCH2CH2TC6H4OCH3. CONHCH2CH2TC6H3(OCH3) 2.

V1. 2- (3,4 dimethoxyphenylthiazole) 4 ethyl phthalimide C6H4 (CO) zNCHzCHzTCsHs (OCI-Is) 2.

VII. 2- (3,4-dimethoxyphenylthiazle) -4-ethylamine NI-IzCHzCHzTCsHs (OCI-Is) 2.

droxyl groups may be in ortho-, meta-or paraposition, and wherein n stands for one of the numbers 1 and 2, and wherein R2 stands for an alkyl group which contains a NHz group, said :5

Experzmental data 5 Nitrogen Number Crystal form I claim: 1. The thiazole compounds of the general formula:

XO R: R(%\ /CR1 N/ 11 wherein R stands for an aliphatic radical which may be substituted by a phenyl radical, and wherein X represents either hydrogen or alkyl, or benzyl, and wherein R1 stands for an'organic radical selected from the group consisting of phenyl, benzyl, lower alkyl substituted phenyl, hydroxy phenyl, lower alkoxy phenyl, alkyl, lower hydroxy alkyl and lower alkoxy alkyl, and wherein n stands for one of the numbers 1 and 2, and wherein R2 stands for an alkyl group which contains a NHz group, said compounds generally being well crystallized in the form of their hydrochloric acid salts.

2. The thiazole compounds of the general formula:

X-o-s u I R: RC\ /CR1 L N/ .Jn

wherein R stands for an aliphatic radical which may be substituted by a phenyl radical, and wherein X represents either hydrogen or alkyl, or benzyl, and wherein R1 represents the phenyl radical which, may contain one or more free or alkyl substituted hydroxyl groups, which hycompounds generally being well crystallized in the form of their hydrochloric acid salts.

3. 2-phenylthiazole-4-ethylamine of the formula:

which boils at 146-14? C. under a pressure of 2-3 mm. and the hydrochloric acid salt of which melts at 9l-92 C. 4. Di- (Z-phenylthiazolel) -1,3 -isopropylamine of the formula:

wa CH2C c0 H a N H2NCH OH2C O CDH5 N 40 which boils at 235-238 C. and the hydrochloric acid salt of which forms needles.

5. 2-p-hydroxyphenylthiazole-4-ethylamine of the formula:

6 HzNCH2OHzO oon N which boils at 218-222 C.

TREAT B. JOHNSON. 

